Is EPM2A p.Ala72Val (c.215C>T) pathogenic?

EPM2A p.Ala72Val (c.215C>T) is classified Uncertain significance in EPM2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-03). Very rare (popmax 8.97e-05%, nfe); Associated with myoclonic epilepsy of Lafora 1.

What condition is associated with EPM2A p.Ala72Val (c.215C>T)?

EPM2A p.Ala72Val (c.215C>T) is associated with myoclonic epilepsy of Lafora 1, progressive myoclonus epilepsy (ClinVar).

How common is EPM2A p.Ala72Val (c.215C>T) in the general population?

EPM2A p.Ala72Val (c.215C>T) is very rare (popmax 8.97e-05%, nfe) (gnomAD).

How is Lafora disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

EPM2A p.Ala72Val

c.215C>T · rs1284392729 · VCV1019461

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.97e-05%, nfe)

Conditions

myoclonic epilepsy of Lafora 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.284	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.48	GERP 0.77
Regional constraint	o/e 1.04	unconstrained · MANE · 108 kb · p 0.41 · regional, not allelic
Overall
CADD	15.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.97e-05% European (non-Finnish) · 1/1,114,948 alleles

Overall 0.000662% 1/151,016 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EPM2A
Protein: p.Ala72Val
Coding: c.215C>T
MANE Select: NM_005670
dbSNP: rs1284392729
Type: single nucleotide variant
Location: chr6:145735284 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 34.25 · 2 PDB
Residue 72: the 'disordered' region; the cbm20 domain

Full EPM2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myoclonic epilepsy of Lafora 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive myoclonus epilepsy

For Lafora disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood
Prevalence: 1-9 / 1 000 000 (France)

Similar variants

EPM2A p.Ala72Thr Uncertain significance ★ same residue
EPM2A c.301+1G>T Pathogenic ★★ same condition
EPM2A c.302-1G>C Pathogenic/Likely pathogenic ★★ same condition
EPM2A c.302-2A>G Pathogenic ★★ same condition
EPM2A p.Arg108Cys Pathogenic/Likely pathogenic ★★ same condition
EPM2A p.Arg171His Pathogenic/Likely pathogenic ★★ same condition
EPM2A p.Arg241Ter Pathogenic/Likely pathogenic ★★ same condition
EPM2A p.Glu56Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/epm2a-p-ala72val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown